The association of CAPN1 316 marker genotypes with growth and meat quality traits of steers finished on pasture

The objective of this paper was to determine the association of a SNP in the μ-calpain gene at position 316 with growth and quality of meat traits of steers grown on pasture. Fifty-nine Brangus and 20 Angus steers were genotyped for CAPN1 316. Warner Bratzler shear force was measured in l. lumborum samples after a 7-day aging period. A multivariate analysis of variance was performed, including shear force (WBSF), final weight (FW), average daily gain (ADG), backfat thickness (BFT), average monthly fat thickness gain (AMFTG), rib-eye area (REA), and beef rib-eye depth (RED) as dependent variables. The CAPN1 316 genotype was statistically significant. Univariate analyses were done with these variables. The marker genotype was statistically significant (p < 0.05) for WBSF (kg: CC: 4.41 ± 0.57; CG: 5.58 ± 0.20; GG: 6.29 ± 0.18), FW (kg: CC: 360.23 ± 14.71; CG: 381.34 ± 5.26; GG: 399.23 ± 4.68), and ADG (kg/d: CC: 0.675 ± 0.046; CG: 0.705 ± 0.016; GG: 0.765 ± 0.014) Shear force, final weight and average daily gain were significantly different according to the CAPN1 316 marker genotypes. The marker genotype was statistically significant in the multivariate analysis (p = 0.001). The first characteristic root explained 89% of the differences among genotypes. WBSF, FW and ADG were the most important traits in the first vector, indicating that animals with the marker genotype for lowest WBSF also have the lowest FW and ADG

Small Molecules Targeted to a Non-Catalytic “RVxF” Binding Site of Protein Phosphatase-1 Inhibit HIV-1

HIV-1 Tat protein recruits host cell factors including CDK9/cyclin T1 to HIV-1 TAR RNA and thereby induces HIV-1 transcription. An interaction with host Ser/Thr protein phosphatase-1 (PP1) is critical for this function of Tat. PP1 binds to a Tat sequence, Q35VCF38, which resembles the PP1-binding “RVxF” motif present on PP1-binding regulatory subunits. We showed that expression of PP1 binding peptide, a central domain of Nuclear Inhibitor of PP1, disrupted the interaction of HIV-1 Tat with PP1 and inhibited HIV-1 transcription and replication. Here, we report small molecule compounds that target the “RVxF”-binding cavity of PP1 to disrupt the interaction of PP1 with Tat and inhibit HIV-1 replication. Using the crystal structure of PP1, we virtually screened 300,000 compounds and identified 262 small molecules that were predicted to bind the “RVxF”-accommodating cavity of PP1. These compounds were then assayed for inhibition of HIV-1 transcription in CEM T cells. One of the compounds, 1H4, inhibited HIV-1 transcription and replication at non-cytotoxic concentrations. 1H4 prevented PP1-mediated dephosphorylation of a substrate peptide containing an RVxF sequence in vitro. 1H4 also disrupted the association of PP1 with Tat in cultured cells without having an effect on the interaction of PP1 with the cellular regulators, NIPP1 and PNUTS, or on the cellular proteome. Finally, 1H4 prevented the translocation of PP1 to the nucleus. Taken together, our study shows that HIV- inhibition can be achieved through using small molecules to target a non-catalytic site of PP1. This proof-of-principle study can serve as a starting point for the development of novel antiviral drugs that target the interface of HIV-1 viral proteins with their host partners

The Double-stranded RNA–dependent Protein Kinase Differentially Regulates Insulin Receptor Substrates 1 and 2 in HepG2 Cells

The RNA-dependent protein kinase (PKR), initially known as a virus infection response protein, is found to differentially regulate two major players in the insulin signaling pathway, IRS1 and IRS2. PKR up-regulates the inhibitory phosphorylation of IRS1 and the expression of IRS2 at the transcriptional level

Exploration of Shared Genetic Architecture Between Subcortical Brain Volumes and Anorexia Nervosa

In MRI scans of patients with anorexia nervosa (AN), reductions in brain volume are often apparent. However, it is unknown whether such brain abnormalities are influenced by genetic determinants that partially overlap with those underlying AN. Here, we used a battery of methods (LD score regression, genetic risk scores, sign test, SNP effect concordance analysis, and Mendelian randomization) to investigate the genetic covariation between subcortical brain volumes and risk for AN based on summary measures retrieved from genome-wide association studies of regional brain volumes (ENIGMA consortium, n = 13,170) and genetic risk for AN (PGC-ED consortium, n = 14,477). Genetic correlations ranged from − 0.10 to 0.23 (all p > 0.05). There were some signs of an inverse concordance between greater thalamus volume and risk for AN (permuted p = 0.009, 95% CI: [0.005, 0.017]). A genetic variant in the vicinity of ZW10, a gene involved in cell division, and neurotransmitter and immune system relevant genes, in particular DRD2, was significantly associated with AN only after conditioning on its association with caudate volume (pFDR = 0.025). Another genetic variant linked to LRRC4C, important in axonal and synaptic development, reached significance after conditioning on hippocampal volume (pFDR = 0.021). In this comprehensive set of analyses and based on the largest available sample sizes to date, there was weak evidence for associations between risk for AN and risk for abnormal subcortical brain volumes at a global level (that is, common variant genetic architecture), but suggestive evidence for effects of single genetic markers. Highly powered multimodal brain- and disorder-related genome-wide studies are needed to further dissect the shared genetic influences on brain structure and risk for AN

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

Stress Responsivity and HPA Axis Activity in Juveniles: Results From a Home-Based CO 2 Inhalation Study

Objective: A previous laboratory-based study found elevated cortisol levels in anxious children susceptible to CO 2 -induced panic, but the effects of parent diagnosis were not considered. The current home-based study tested the hypothesis that parental panic disorder and offspring response to CO 2 are associated with elevated cortisol levels in juvenile offspring. Method: A total of 131 offspring (ages 9–19) of parents with panic disorder, major depression, and no mental disorder underwent CO 2inhalation. Parent and child diagnoses were assessed. Salivary cortisol was assayed before and after CO2 inhalation. Results: Neither parents with panic disorder, parents with major depression, or offspring anxiety predicted offspring cortisol levels. Independent of parent and child diagnoses, anxiety response to CO 2 predicted elevated cortisol levels in offspring. Conclusions: As in adults, anxiety response to CO 2 in juveniles is associated with elevated cortisol levels, but elevated cortisol levels are not related to parent or child diagnoses